Associate editor: D. Hoyer
Nicotinic acetylcholine receptors: From basic science to therapeutics

https://doi.org/10.1016/j.pharmthera.2012.08.012Get rights and content

Abstract

Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors.

The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic ‘drug-like’ molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic.

Section snippets

Introduction, brief history of nicotine and nicotinic acetylcholine receptors

As in the Sisyphean myth it might seem as if obtaining more knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) brings us first one step closer to the top of the knowledge hill before rolling back to see only more questions remaining. Progress made during the past twenty years has charted a course marked by the discovery of genes encoding nAChRs, by a better grasp of their pharmacology and by the identification of the receptors associated with neurological diseases. However, at the

Structure of neuronal nicotinic acetylcholine receptors: from genes to proteins

The isolation and purification of the protein corresponding to the muscle nAChR from the Torpedo electric organ by Jean-Pierre Changeux allowed a first reading of the corresponding amino acid sequence (Changeux et al., 1970). At the same time, spectacular progress in the field of molecular biology made it possible to identify and clone the gene encoding for the α subunit of the muscle receptor (Noda et al., 1983). Soon thereafter, the five genes encoding for the α1, β1, γ, δ and ε subunits were

Receptor distribution, genetics and disease

To appreciate the physiological role of nAChRs it is of crucial importance to have a thorough knowledge of both their macroscopic distribution, i.e. where subtypes are expressed in the nervous system, in tissues and organs, and their microscopic, subcellular distribution. In addition, the receptor distribution is important for understanding the relationship between receptor dysfunction and nervous system disorders.

Function and biophysical properties

Like all cell-surface ligand-gated ion channels, nAChRs modulate the flow of ions across the cell membrane and are under the control of an extracellular signaling molecule. A net influx of cations through the associated channel pore depolarizes the cell membrane and increases neuronal excitability. Calcium entry through some nAChRs produces additional effects on an array of intracellular signaling cascades. ACh, the natural endogenous ligand of nAChRs, is released from presynaptic cholinergic

Neuronal nicotinic acetylcholine receptor ligands in the clinic and in development

Nicotinic compounds that have shown promise as therapeutic agents are discussed below by the disease they target and are listed in Table 2 according to their development status. Compounds that have been discontinued for one or more indications are also included, since these may provide important clues as to why nicotinic drugs have failed for a certain indication. The bold numbers in brackets after a compound in the text below refer to the compound numbers in Table 2.

Selected preclinical and

The future of neuronal nicotinic acetylcholine receptor pharmacology and nicotinic drugs

Discoveries in the field of nAChRs have led to a step-wise progress in our understanding of these ligand gated ion channels, from the discovery of genes encoding for nAChRs, the identification of their physiological effects in the central nervous system, to the identification of gene associated diseases. These findings raised hope that new therapeutic avenues could be discovered that would result in the development of molecules targeting a wide range of disorders, from pain to cognitive

Conflict of interest statements

All authors declare that this review was prepared without external support. Daniel Bertrand and Hans Rollema have received payments as consultants for Pfizer Inc. Raymond Hurst is an employee of Pfizer Worldwide Research & Development.

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